The type 1 diabetes (T1D) is an autoimmune disease that is caused by the permanent destruction of insulin- producing beta cells in pancreas by self-attacking immune cells. These self-attacking immune T cells are generally eliminated during development stage, and should be tolerized in the periphery if any leaking occurs. Therefore, a failure in the induction/maintenance of T-cell tolerance is crucial for T1D. However, the molecular mechanisms by which T-cell tolerance is induced/maintained remain largely unknown. Here we have found that loss of Sirt1 functions causes abnormally elevated immune responses and a break-down of peripheral tolerance of T cells. As a consequence, Sirt1-/- mice develop spontaneous autoimmunity. Those results indicate that Sirt1 is a negative regulator of T-cell activation and is required to maintain T-cell tolerance. It is therefore possible that mice without Sirt1 may develop T1D. Activation of Sirt1 by small molecules like resveratrol can potentially be used to treat T1D by inhibiting beta-cell-attacking autoimmune T cells. Indeed, results from a pilot study in our laboratory indicate that the activator of Sirt1, resveratrol, protected NOD mice from T1D. Therefore, this proposal aims to determine the molecular mechanisms underlying how Sirt1 functions an anergic factor of T-cells, and to investigate how dysregulated Sirt1 functions are involved in the development of T1D. We will also further determine the preventive/treating effects of resveratrol on T1D. Results from our proposed research are likely to uncover a novel molecular mechanism of T-cell tolerance. This study will also indentify potential therapeutic reagents for T1D.